Mobilization of tissue-resident lymphocytes during secondary infection

T细胞在清除病原体方面起着关键作用，而记忆性T细胞的产生是一种 在防止二次感染方面的重要组成部分。记忆性T细胞可以广泛地 根据它们的位置分为两组，那些能够在 身体和那些滞留在组织中的人，准备对二次感染做出快速反应。 组织驻留记忆T细胞(Trm)细胞保留在组织中，不会被 感染后的循环细胞消失。循环中的T细胞通常不足以保护 避免二次感染；因此，确定如何最大化 Trm细胞的数量和功能，因为它们对强大的组织特异性免疫至关重要。仅限 少数微生物需要突破粘膜表面才能引发疾病；然而， 已建立的Trm种群检测和迁移到新的感染区的机制 仍未被探索。我们早期的工作是使用肠道细菌耶尔森氏菌 假性结核(Yptb)，在肠道中发现了两个不同的CD8 Trm群体，这两个群体 通过其整合素CD103的表达而分化。CD103neg Trm细胞优先定位 到围绕感染区域形成的淋巴细胞团，限制病原体复制，但 在感染消除后消散。CD103-neg-CD4和CD8-Trm群体也很丰富 在其他组织中，但它们在组织特异性免疫中的各自作用仍知之甚少。 我们假设驻留在组织中的淋巴细胞群体的多样性是一种功能 异质性，CD103neg淋巴细胞亚群能够在 对组织特异性信号的反应，这些信号提醒他们注意致病侮辱，并形成 在二次挑战期间，淋巴细胞团在新的感染区域周围形成。这些 研究将利用光转换来标记组织驻留细胞，并允许我们跟踪细胞 动态平衡和肠道感染期间的迁移。我们将利用这项技术来解决 我们对Trm生物学知识的基本差距包括：(1)Trm多样性如何与 继发感染期间的功能结果以及(2)识别由以下因素产生的信号 对感染作出反应的组织，推动Trm动员和病原体控制。这些 实验有可能极大地提高我们对组织驻留的理解 淋巴细胞生物学以及如何调整免疫策略以改善Trm功能。

T cells play a critical role in eliminating pathogens and the generation of memory T cells is an important component in protection from secondary infection. Memory T cells can be broadly divided into two groups based on their location, those that are capable of circulating throughout the body and those that are lodged in tissues, poised to respond rapidly to secondary infection. Tissue-resident memory T cells (Trm) cells remain in the tissue and are not replenished by circulating cells after infection is resolved. Circulating T cells are often not sufficient to protect from secondary infection; therefore, it is of significant interest to determine how to maximize the number and functionality of Trm cells as they are critical for robust tissue-specific immunity. Only a small number of microbes need to breach the mucosal surface to initiate disease; however, the mechanism by which established Trm populations detect and migrate to new areas of infection remains unexplored. Our earlier work, using the intestinal bacterial pathogen Yersinia pseudotuberculosis (Yptb), identified two distinct CD8+ Trm populations in the intestine that are differentiated by their expression of the integrin CD103. CD103neg Trm cells preferentially localize to lymphocyte clusters that form around areas of infection and limit pathogen replication, but dissipate after infection is resolved. CD103neg CD4+ and CD8+ Trm populations are also abundant in other tissues, but their respective roles in tissue-specific immunity remain poorly understood. We hypothesize the diversity in the tissue-resident lymphocyte population underlies a functional heterogeneity, with the CD103neg subset of lymphocytes capable of localized migration in response to tissue-specific signals that alert them to a pathogenic insult and forms the basis for lymphocyte cluster formation around new areas of infection during secondary challenge. These studies will utilize photoconversion to mark tissue-resident cells and allowing us to track cellular migration during homeostasis and intestinal infection. We will leverage this technique to address fundamental gaps in our knowledge of Trm biology including: (1) how Trm diversity relates to functional outcomes during secondary infection and (2) the identification of signals generated by the tissue in response to infection that drive Trm mobilization and pathogen control. These experiments have the potential to significantly advance our understanding of tissue-resident lymphocyte biology and how immunization strategies can be tailored to improve Trm functionality.